PROJECT SUMMARY/ABSTRACT Heart failure (HF) is the most common reason for hospitalization in older adults. Over 85% of all patients hospitalized with HF are 65 years of age or older. Multimorbidity, typically defined as the presence of ?2 chronic conditions, increases the risks of hospitalization and death in older HF patients, and greatly complicates the clinical management of HF. Caution is required in applying national clinical practice guidelines to the care of older adults with multimorbidity, as this could result in undesirable net effects and less than optimal outcomes including adverse interactions between drugs and various concomitant diseases. In response to PA-17-088 (Exploratory Analyses of Existing Cohorts, Data Sets, and Stored Biospecimens to Address Clinical Aging Research Questions, R01), we propose to leverage an existing HF cohort, including data for more than 100,000 patients with HF within the Cardiovascular Research Network between 2005-2012, with follow-up data up to 2017. We will extend our previous efforts by examining treatment patterns and the net benefits versus harms of selected therapies in older adults with HF and a wide spectrum of multimorbidity burden. We will further examine the benefits and adverse outcomes of various therapies focusing on particularly vulnerable subgroups of patients with HF afflicted by two prevalent conditions, anemia or diabetes. Our specific aims are: (1) to examine the effectiveness of selected medical therapies (renin-angiotensin- aldosterone system blockers, beta-blockers, diuretics, and aldosterone receptor blockers) on death, HF hospitalization, and all-cause hospitalizations in a large, community-based population of older adults with HF across a range of levels of multimorbidity burden and left ventricular ejection fraction; (2) to evaluate targeted adverse outcomes, including kidney dysfunction, hyperkalemia, sodium disturbances, bradycardia, and syncope associated with selected HF therapies in older adults with HF, stratified by multimorbidity burden and left ventricular ejection fraction status; and (3) to characterize the potential benefits and adverse outcomes associated with selected HF therapies in older adults with HF and two prevalent comorbidity dyads?HF- diabetes and HF-anemia?that are common and substantially increase the risks of death and morbidity. In addition, we will create novel, validated methods to identify adverse outcomes related to HF therapies from unstructured data in large electronic health record systems through natural language processing technology, along with employing state-of-the-art analytic approaches to evaluate treatment-related outcomes. In that our proposed investigation will take advantage of a large, geographically and demographically diverse cohort of adults with HF receiving care within community-based healthcare delivery systems, we anticipate our findings will be highly generalizable to the broad spectrum of older adults with HF managed in ?real-world? practice settings.